In the study, we demonstrate a similar anti-fibrosis effect of bortezomib in bleomycin-induced pulmonary fibrosis model and reveal an immunoregulatory mechanism that bortezomib significantly decreases the ratio and quantity of Arg1+ macrophages and restrains subsequent CXCL16 secretion-associated CXCR6+ CD4 T accumulation, suggesting that M2 macrophages may show high sensitivity to bortezomib. Here, CXCL16 is linked to pulmonary fibrosis.